VHLbox

VHLbox is a conserved protein motif named for its association with the von Hippel-Lindau (VHL) tumor suppressor protein. It is found in VHL and other VHL-like substrate receptor proteins that assemble with Elongin B and Elongin C to form the CRL2 ubiquitin ligase complex. The VHL-box is a short region, typically about 40–60 amino acids, located toward the C-terminal portion of these proteins and contributes to recruitment of the cullin-2–Rbx1 core ligase through interactions with Elongin B/C and other complex components. The motif often occurs in conjunction with the BC-box, a separate interaction motif that also mediates Elongin B/C binding; together these elements define VHL-like substrate receptors used by CRL2 to ubiquitylate target proteins.

Functionally, CRL2–VHL complexes ubiquitylate substrates according to the receptor’s specificity, directing them to proteasomal degradation. In the canonical VHL protein, recognition of hydroxylated HIF-α leads to its ubiquitylation and degradation under normoxic conditions; other VHL-box–containing receptors expand the range of substrates that can be processed by CRL2.

Evolution and annotation, the VHL-box is conserved across diverse species and is recognized by protein-domain databases to annotate VHL-like CRL2 substrate receptors. It is used in bioinformatics studies of ubiquitin ligases and in predictive models of protein–protein interactions.

Clinical relevance: The VHL gene is a clinically important tumor suppressor, and disruptions in the VHL–CRL2 pathway can contribute to tumor development via dysregulated hypoxia signaling. The VHL-box itself is primarily a structural feature used to understand CRL2 assembly rather than a direct therapeutic target.

See also: von Hippel-Lindau, CRL2, Elongin B/C, BC-box, ubiquitin-proteasome system.